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Efficacy and Safety of Acoramidis (AG10) in Subjects With Transthyretin Amyloid Polyneurophathy (ATTRibute-PN)

Primary Purpose

Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy

Status
Withdrawn
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Acoramidis
Sponsored by
Eidos Therapeutics, a BridgeBio company
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy focused on measuring TTR, ATTR-PN, Familial ATTR-PN, Amyloidosis, Amyloid, Transthyretin, Polyneuropathy, TTR-mediated amyloidosis, Amyloidosis, hereditary, Familial Amyloid Polyneuropathies, Amyloidosis, Hereditary, Transthyretin-Related

Eligibility Criteria

18 Years - 90 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male or female ≥18 to ≤90 years of age;
  • Have Stage I or II symptoms (polyneuropathy disability [PND] ≤IIIb) of ATTR-PN and an established diagnosis of ATTR-PN as defined by physical examination findings and/or neurophysiological test findings consistent with the diagnosis of ATTR-PN;
  • Have an NIS of 5 to 130 (inclusive) during Screening;
  • Have a nerve conduction studies (NCS) score (sum of the sural sensory nerve action potential [SNAP], tibial compound muscle action potential (CMAP), ulnar SNAP, ulnar CMAP, and peroneal CMAP) of ≥2 points during Screening. NCS is a component of mNIS+7;
  • Have a mutation consistent with ATTR-PN either documented in medical history or confirmed by genotyping obtained at Screening prior to enrollment. No genetic testing is needed for subjects who are recipients of domino liver transplants;
  • Have an anticipated survival of >2 years in the opinion of the investigator;
  • Have Karnofsky performance status ≥60 %.

Exclusion Criteria:

  • Had a prior liver transplantation or is planning to undergo liver transplantation with a wild-type organ graft as treatment for symptomatic ATTR-PN during the study period. Note: Recipients of a "domino" liver transplant from an ATTR-PN donor who have developed ATTR-PN mediated by their graft are allowed under this protocol, as long as re-transplantation to treat ATTR-PN is not planned during the study period and meets all other eligibility criteria;
  • Has sensorimotor or autonomic neuropathy not related to ATTR-PN; for example, due to autoimmune disease or monoclonal gammopathy, malignancy, or alcohol abuse;
  • Has Vitamin B-12 levels below the lower limit of normal (LLN) at Screening;
  • Has clinical evidence of untreated hyperthyroidism or hypothyroidism;
  • Has leptomeningeal TTR amyloidosis;
  • Has Type 1 diabetes;
  • Has had Type 2 diabetes for ≥5 years;
  • Has a documented case of hepatitis B or C at Screening;
  • Known history of human immunodeficiency virus (HIV) infection;
  • Has NYHA heart failure classification >Class II;
  • Had acute coronary syndrome, uncontrolled cardiac arrhythmia, or a stroke within 90 days prior to Screening;
  • Has estimated glomerular filtration rate (eGFR) by Modification of Diet for Renal Disease (MDRD) formula <30 mL/min/1.73 m2 at Screening;
  • Has abnormal liver function tests at Screening, defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × upper limit of normal (ULN) or total bilirubin >3 × ULN;
  • Had a malignancy within 2 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated;
  • Has known hypersensitivity to acoramidis, its metabolites, or formulation excipients.
  • Is currently undergoing treatment for ATTR-PN with tafamidis, or patisiran, inotersen, or other knockdown agents, marketed drug products lacking a labeled indication for ATTR-PN (e.g., diflunisal, doxycycline), natural products or derivatives used as unproven therapies for ATTR-PN (e.g., green tea extract ,tauroursodeoxycholic acid [TUDCA]/ursodiol), within 14 days, or 14 days for tafamidis or 90days for patisiran and 180 days for inotersen prior to dosing.

Sites / Locations

    Arms of the Study

    Arm 1

    Arm Type

    Experimental

    Arm Label

    Acoramidis HCI 800 mg (two 400mg tablets)

    Arm Description

    TTR stabilizer administered orally twice daily (BID)

    Outcomes

    Primary Outcome Measures

    Change from baseline to Month 18 in mNIS+7
    To determine the efficacy of acoramidis in subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN) by evaluating the change in Modified Neuropathy Impairment Score +7 (mNIS+7) from baseline to 18 months.
    Safety: TESAEs will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN)
    To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN)
    Safety: Adverse Events leading to treatment discontinuation will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN)
    To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN)
    Safety: Adverse Events will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN)
    To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN)
    Safety: Incidence of abnormal physical exam will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN)
    To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN)
    Safety: Incidence of abnormal vital signs will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN)
    To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN)
    Safety: Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN)
    To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN)

    Secondary Outcome Measures

    Change from baseline to Month 18 in Norfolk QOL-DN
    To evaluate the effects of acoramidis in subjects with symptomatic ATTR-PN on Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN)
    Change from baseline to Month 18 in mBMI
    To evaluate the effects of acoramidis in subjects with symptomatic ATTR-PN on Modified body mass index (mBMI)
    Change from baseline to Month 18 in COMPASS-31
    To evaluate the effects of acoramidis in subjects with symptomatic ATTR-PN on Composite Autonomic Score (COMPASS-31)

    Full Information

    First Posted
    April 29, 2021
    Last Updated
    January 26, 2022
    Sponsor
    Eidos Therapeutics, a BridgeBio company
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    1. Study Identification

    Unique Protocol Identification Number
    NCT04882735
    Brief Title
    Efficacy and Safety of Acoramidis (AG10) in Subjects With Transthyretin Amyloid Polyneurophathy (ATTRibute-PN)
    Official Title
    A Phase 3, Open-Label, Multicenter, Single-Arm Study to Evaluate the Efficacy and Safety of Acoramidis in Subjects With Symptomatic Transthyretin Amyloid Polyneuropathy (ATTRibute-PN Study)
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    January 2022
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    Sponsor's decision to cancel study
    Study Start Date
    September 2021 (Anticipated)
    Primary Completion Date
    September 2026 (Anticipated)
    Study Completion Date
    October 2026 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    Eidos Therapeutics, a BridgeBio company

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Product Manufactured in and Exported from the U.S.
    Yes
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    Phase 3 efficacy and safety of acoramidis in subjects with symptomatic Transthyretin Amyloid Polyneuropathy (ATTR-PN)
    Detailed Description
    Transthyretin amyloid polyneuropathy (ATTR-PN), also called "Familial Transthyretin-Mediated Amyloid Polyneuropathy (FAP)" is a hereditary condition caused by mutations in the TTR gene. It is estimated that around 10,000 people in the world are affected. In ATTR-PN, amyloid builds up in the nerves that detect temperature, pain, and touch. Patients with ATTR-PN can experience a loss of sensation, tingling, numbness, or pain in the hands and feet (also called peripheral neuropathy). In this study Eidos, a BridgeBio Company, is researching the investigational drug acoramidis (AG10) hydrochloride (HCl) 800mg administered orally twice a day. Through the study, Eidos/BridgeBio wants to evaluate the efficacy and safety of acoramidis in patients with ATTR-PN. The primary outcome of the study is to determine the efficacy of acoramidis in the treatment of subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN). At the end of 18 months, participants will be eligible to continue to receive acoramidis to evaluate the long-term safety and tolerability of acoramidis.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Transthyretin-Related (ATTR) Familial Amyloid Polyneuropathy
    Keywords
    TTR, ATTR-PN, Familial ATTR-PN, Amyloidosis, Amyloid, Transthyretin, Polyneuropathy, TTR-mediated amyloidosis, Amyloidosis, hereditary, Familial Amyloid Polyneuropathies, Amyloidosis, Hereditary, Transthyretin-Related

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Single Group Assignment
    Masking
    None (Open Label)
    Allocation
    N/A
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Acoramidis HCI 800 mg (two 400mg tablets)
    Arm Type
    Experimental
    Arm Description
    TTR stabilizer administered orally twice daily (BID)
    Intervention Type
    Drug
    Intervention Name(s)
    Acoramidis
    Other Intervention Name(s)
    AG10
    Intervention Description
    TTR stabilizer administered orally twice daily (BID)
    Primary Outcome Measure Information:
    Title
    Change from baseline to Month 18 in mNIS+7
    Description
    To determine the efficacy of acoramidis in subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN) by evaluating the change in Modified Neuropathy Impairment Score +7 (mNIS+7) from baseline to 18 months.
    Time Frame
    18 Months
    Title
    Safety: TESAEs will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN)
    Description
    To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN)
    Time Frame
    60 Months
    Title
    Safety: Adverse Events leading to treatment discontinuation will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN)
    Description
    To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN)
    Time Frame
    60 Months
    Title
    Safety: Adverse Events will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN)
    Description
    To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN)
    Time Frame
    60 Months
    Title
    Safety: Incidence of abnormal physical exam will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN)
    Description
    To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN)
    Time Frame
    60 Months
    Title
    Safety: Incidence of abnormal vital signs will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN)
    Description
    To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN)
    Time Frame
    60 Months
    Title
    Safety: Columbia-Suicide Severity Rating Scale (C-SSRS) will be used to evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic polyneuropathy (ATTR-PN)
    Description
    To evaluate the long-term safety and tolerability of acoramidis administered to subjects with symptomatic transthyretin amyloid polyneuropathy (ATTR-PN)
    Time Frame
    60 Months
    Secondary Outcome Measure Information:
    Title
    Change from baseline to Month 18 in Norfolk QOL-DN
    Description
    To evaluate the effects of acoramidis in subjects with symptomatic ATTR-PN on Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QOL-DN)
    Time Frame
    18 Months
    Title
    Change from baseline to Month 18 in mBMI
    Description
    To evaluate the effects of acoramidis in subjects with symptomatic ATTR-PN on Modified body mass index (mBMI)
    Time Frame
    18 Months
    Title
    Change from baseline to Month 18 in COMPASS-31
    Description
    To evaluate the effects of acoramidis in subjects with symptomatic ATTR-PN on Composite Autonomic Score (COMPASS-31)
    Time Frame
    18 Months

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Maximum Age & Unit of Time
    90 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Male or female ≥18 to ≤90 years of age; Have Stage I or II symptoms (polyneuropathy disability [PND] ≤IIIb) of ATTR-PN and an established diagnosis of ATTR-PN as defined by physical examination findings and/or neurophysiological test findings consistent with the diagnosis of ATTR-PN; Have an NIS of 5 to 130 (inclusive) during Screening; Have a nerve conduction studies (NCS) score (sum of the sural sensory nerve action potential [SNAP], tibial compound muscle action potential (CMAP), ulnar SNAP, ulnar CMAP, and peroneal CMAP) of ≥2 points during Screening. NCS is a component of mNIS+7; Have a mutation consistent with ATTR-PN either documented in medical history or confirmed by genotyping obtained at Screening prior to enrollment. No genetic testing is needed for subjects who are recipients of domino liver transplants; Have an anticipated survival of >2 years in the opinion of the investigator; Have Karnofsky performance status ≥60 %. Exclusion Criteria: Had a prior liver transplantation or is planning to undergo liver transplantation with a wild-type organ graft as treatment for symptomatic ATTR-PN during the study period. Note: Recipients of a "domino" liver transplant from an ATTR-PN donor who have developed ATTR-PN mediated by their graft are allowed under this protocol, as long as re-transplantation to treat ATTR-PN is not planned during the study period and meets all other eligibility criteria; Has sensorimotor or autonomic neuropathy not related to ATTR-PN; for example, due to autoimmune disease or monoclonal gammopathy, malignancy, or alcohol abuse; Has Vitamin B-12 levels below the lower limit of normal (LLN) at Screening; Has clinical evidence of untreated hyperthyroidism or hypothyroidism; Has leptomeningeal TTR amyloidosis; Has Type 1 diabetes; Has had Type 2 diabetes for ≥5 years; Has a documented case of hepatitis B or C at Screening; Known history of human immunodeficiency virus (HIV) infection; Has NYHA heart failure classification >Class II; Had acute coronary syndrome, uncontrolled cardiac arrhythmia, or a stroke within 90 days prior to Screening; Has estimated glomerular filtration rate (eGFR) by Modification of Diet for Renal Disease (MDRD) formula <30 mL/min/1.73 m2 at Screening; Has abnormal liver function tests at Screening, defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >3 × upper limit of normal (ULN) or total bilirubin >3 × ULN; Had a malignancy within 2 years, except for basal or squamous cell carcinoma of the skin or carcinoma in situ of the cervix that has been successfully treated; Has known hypersensitivity to acoramidis, its metabolites, or formulation excipients. Is currently undergoing treatment for ATTR-PN with tafamidis, or patisiran, inotersen, or other knockdown agents, marketed drug products lacking a labeled indication for ATTR-PN (e.g., diflunisal, doxycycline), natural products or derivatives used as unproven therapies for ATTR-PN (e.g., green tea extract ,tauroursodeoxycholic acid [TUDCA]/ursodiol), within 14 days, or 14 days for tafamidis or 90days for patisiran and 180 days for inotersen prior to dosing.
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Mark McGovern, RN, CCRN
    Organizational Affiliation
    Eidos Therapeutics, a BridgeBio company
    Official's Role
    Study Director

    12. IPD Sharing Statement

    Learn more about this trial

    Efficacy and Safety of Acoramidis (AG10) in Subjects With Transthyretin Amyloid Polyneurophathy (ATTRibute-PN)

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